ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is the most common life threatening hereditary disease in the United States, affecting an estimated 1 in 500 people. Approximately 50% of ADPKD patients develop end-stage renal disease (ESRD) by 50 years of age, and ADPKD accounts for 5-10% of ESRD in the United States and Europe. Affected patients may be asymptomatic for many years despite radiographic evidence of marked architectural distortion of renal parenchyma. Therefore, there is an immediate need for specific and sensitive biomarkers that are early predictors of disease severity and progression. We hypothesize that changes in the production of bioactive lipids will correlate with severity and progression of ADPKD. Validated targeted mass spectrometry-based approaches will be used to identify and validate biomarkers in HALT PKD trial patient samples. In our previous studies, we have identified several bioactive lipid markers that associated with the progression of ADPKD (assessed as the increase in total kidney volume over a period of 3 years) in children and young adults with normal renal function. In this study we will validate these lipid peroxidation products as predictive markers of disease progression. In the last step, we will identify mechanisms that contribute to the changes in biomarkers through a redox proteomics tool. Pathway and network analysis will provide insights into novel pathophysiological pathways of disease progression. Ultimately such knowledge can be applied towards the stratification of patients based upon their rate of disease progression and towards the development of novel interventions for treatment of ADPKD.